KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression
Xinmiao Tang, Peiwei Wang, Rongli Zhang, Ippei Watanabe, Eugene Chang, Vinesh Vinayachandran, Lalitha Nayak, Stephanie Lapping, Sarah Liao, Annmarie Madera, David R. Sweet, Jiemeng Luo, Jinsong Fei, Hyun-Woo Jeong, Ralf H. Adams, Teng Zhang, Xudong Liao, Mukesh K. Jain
Xinmiao Tang, Peiwei Wang, Rongli Zhang, Ippei Watanabe, Eugene Chang, Vinesh Vinayachandran, Lalitha Nayak, Stephanie Lapping, Sarah Liao, Annmarie Madera, David R. Sweet, Jiemeng Luo, Jinsong Fei, Hyun-Woo Jeong, Ralf H. Adams, Teng Zhang, Xudong Liao, Mukesh K. Jain
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Research Article Cardiology Inflammation

KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression

Abstract

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II–induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

Authors

Xinmiao Tang, Peiwei Wang, Rongli Zhang, Ippei Watanabe, Eugene Chang, Vinesh Vinayachandran, Lalitha Nayak, Stephanie Lapping, Sarah Liao, Annmarie Madera, David R. Sweet, Jiemeng Luo, Jinsong Fei, Hyun-Woo Jeong, Ralf H. Adams, Teng Zhang, Xudong Liao, Mukesh K. Jain

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Figure 1

Heart failure is associated with reduced KLF2 expression in circulating leukocytes and neutrophils.

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Heart failure is associated with reduced KLF2 expression in circulating ...
(A) Klf2 mRNA expression in human peripheral blood leukocytes (n = 8) and neutrophils (n = 7–8). HF, patients with heart failure (n = 15); non-HF, age-matched patients without heart failure (n = 16). (B) Klf2 mRNA expression in peripheral blood leukocytes and neutrophils from WT mice with AngII (1.0 μg/kg/min) or PBS (sham) infusion (n = 5–8). (C) KLF2-tag mice were generated using the CRISPR/Cas9 method. Protein levels of 3×FLAG-KLF2 in blood neutrophils were detected by M2 anti-FLAG antibody (Sigma-Aldrich, F3165). Each lane represents 1 animal. (D and E) Mouse bone marrow–derived neutrophils treated with AngII (100 nmol/L) in vitro (n = 5–7). P values are from 2-tailed, unpaired Student’s t test (A, B, and E) or 1-way ANOVA with Tukey’s post hoc test (D).